U.S. Pat. No. 5,747,498 discloses 4-(substituted phenylamino) quinazoline derivatives, processes for their preparation, pharmaceutical compositions in which they are present and a method of use thereof. These compounds are Tyrosine Kinase Inhibitors and are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. Among them, erlotinib hydrochloride, chemically N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride is a selective inhibitor of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), and is useful for the treatment of proliferative disorders, such as cancers, particularly non small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, head cancer or neck cancer. Erlotinib is represented by the following structure:

Various processes for the preparation of erlotinib and related compounds are disclosed in U.S. Pat. No. 5,747,498, European Patent Application No. 1044969 A2, PCT Patent Publication No. WO 01/34574 A1 and PCT Patent Publication No. WO 2007/060691 A2.
As per the process described in U.S. Pat. No. 5,747,498 (hereinafter “the '498 patent”), erlotinib hydrochloride can be prepared by the reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline, obtained by reaction of 6,7-bis(2-methoxy-ethoxy)-quinazolone with oxalylchloride in a solvent system containing chloroform and dimethylformamide, with 3-ethynylaniline or its hydrochloride salt in a solvent such as a (C1-C6)-alcohol, dimethylformamide, N-methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, pyridine or another aprotic solvent, preferably isopropyl alcohol; in the presence or absence of a base, preferably an alkali or alkaline earth metal carbonate or hydroxide or a tertiary amine base, such as pyridine, 2,6-lutidine, collidine, N-methyl-morpholine, triethylamine, 4-dimethylamino-pyridine or N,N-dimethylaniline; at a temperature from about ambient to about the reflux temperature of the solvent, preferably from about 35° C. to about reflux; under an inert atmosphere such as dry nitrogen. The crude erlotinib hydrochloride (residue) obtained is then basified with saturated aqueous NaHCO3 in the presence of methanol and chloroform followed by flash chromatography on silica using 30% acetone in hexane to afford erlotinib free base, which is further treated with hydrochloric acid in the presence of diethyl ether and chloroform to give erlotinib hydrochloride.
Erlotinib hydrochloride obtained by the process described in the '498 patent is not satisfactory from a purity point of view. The yield of erlotinib hydrochloride obtained according to the process described in the '498 patent is very poor and the process involves column chromatographic purifications. Methods involving column chromatographic purifications cannot be used for large-scale operations, thereby making the process commercially not viable.
According to European Patent No. 1044969, erlotinib hydrochloride is prepared, either by (i) reacting 6,7-bis(2-methoxyethoxy)-N43-[(trimethylsilyl)ethynyl]phenyl-4-quinazolinamine monohydrochloride, obtained by the reaction of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline with a solution of 3-[(trimethylsilyl)ethynyl]aniline in 2-propanol at reflux, with tetra-n-butylammonium fluoride in an aprotic solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, toluene, dichloromethane and chloroform, and then treating the reaction mass with concentrated hydrochloric acid in 2-propanol; or (ii) reacting 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol or its monohydrochloride salt, obtained by the reaction of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline with 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol in acetonitrile at reflux, with an alkali-metal or alkaline-metal hydroxide such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, in an alcoholic solvent such as 1-butanol, 2-butanol and 2-propanol, and then treating the reaction mass with concentrated hydrochloric acid in an alcoholic solvent.
The synthetic routes of erlotinib hydrochloride as described in European Patent No. 1044969 involve lengthy processes and expensive raw materials, and the yields obtained in these routes are not satisfactory, thereby making the processes commercially not viable.
PCT Patent Publication No. WO 99/55683 discloses erlotinib mesylate anhydrate and hydrate polymorphic forms, their method of preparation and pharmaceutical compositions containing thereof.
PCT Patent Publication No. WO 01/34574 A1 describes a process for the preparation of erlotinib hydrochloride in crystalline polymorphic form B, which comprises: a) reacting 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline, obtained by reaction of 4-hydroxy-6,7-bis(2-methoxyethoxy)quinazoline with thionyl chloride in a solvent mixture of methylene chloride and dimethylformamide, with 3-ethynylaniline, prepared by reaction of 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol with a suspension of sodium hydroxide (or potassium hydroxide, or a combination) in toluene with heating, to give N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride; b) recrystallizing the N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride, in a solvent comprising alcohol and water, into the polymorphic form B.
PCT Patent Publication No. WO 2007/060691 A2 describes an improved process for the preparation of erlotinib hydrochloride, which comprises: i) reacting 6,7-dimethoxy-4-(3H)-quinazolinone with aqueous hydrobromic acid or pyridine hydrochloride at an elevated temperature to get a hydrobromide or hydrochloride salt of 6,7-dihydroxy-4-(3H)-quinazolinone which on neutralization with a base gives 6,7-dihydroxy-4-(3H)-quinazolinone; ii) acylating the dihydroxy compound using an acylating agent at a temperature in the range of 20-150° C. and in the presence of a catalyst to give 6,7-diacetoxy-4-(3H)-quinazolinone; iii) reacting the diacetoxy compound with oxalyl chloride at a temperature of 10-100° C. to give 4-chloro-6,7-diacetoxy-quinazoline; iv) condensing the reaction mass containing the chloro compound with 3-ethynylaniline in an organic solvent selected from chloroform, methylene chloride, acetonitrile, isopropyl alcohol, toluene, tetrahydrofuran, dioxane, cyclohexane and dimethylformamide, at a temperature of 10-100° C. to give N-(3-ethynylphenyl)-6,7-diacetoxy-4-quinazolinamine hydrochloride which on further treatment with a base such as aqueous sodium or potassium hydroxide, or aqueous ammonia solution in alcohols at a temperature of 20-60° C. gives N-(3-ethynylphenyl)-6,7-hydroxy-4-quinazolinamine; v) reacting the N-(3-ethynylphenyl)-6,7-hydroxy-4-quinazolinamine with 2-halo-ethylmethyl ether in the presence of a base at a temperature of 25-100° C. to give crude erlotinib base; vi) recrystallizing the crude erlotinib base from different solvents like ethyl acetate, acetonitrile, isopropyl alcohol, methanol, ethanol, acetone, methyl ethyl ketone, water or a mixture thereof to give pure erlotinib base; vii) reacting pure erlotinib base by dissolving or suspending in an organic solvent or water or a mixture thereof with aqueous hydrochloric acid or hydrogen chloride gas dissolved in an organic solvent selected from chloroform, toluene, ethanol, methanol, isopropyl alcohol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, dimethylformamide, dimethyl ether, diethyl ether and tetrahydrofuran to give erlotinib hydrochloride.
The synthetic route of erlotinib hydrochloride described in PCT Patent Publication No. WO 2007/060691 A2 involves a lengthy process, and the yields obtained in this route are very low.
Erlotinib obtained by the processes described in the art is not satisfactory from a purity point of view. We have repeated the erlotinib synthetic procedures as described in the prior art mentioned above and found that relatively large amounts of impurities were obtained along with erlotinib. Among these impurities, the N-methoxyethyl impurity, namely N-[(3-ethynylphenyl)-(2-methoxyethyl)]-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, of formula I:
was identified and isolated. In a specific run, we have found that erlotinib prepared by the above procedures contained about above 0.15% of the N-methoxyethyl impurity at about 1.1 Relative Retention Time (RRT) measured by High Performance Liquid Chromatography (HPLC), which could not be eliminated by re-crystallization, hence the only way to purify erlotinib was by column chromatography.
However, a need still remains for an improved and commercially viable process of preparing pure erlotinib hydrochloride that should solve the aforesaid problems associated with processes described in the prior art, which will be suitable for large-scale preparation, in terms of simplicity, chemical yield and purity of the product.
Extensive experimentation has been carried out by the present inventors to find the way to eliminate this N-methoxyethyl impurity. As a result, it has been found that the N-methoxyethyl impurity formed in the preparation of the erlotinib hydrochloride can be reduced or avoided by isolating erlotinib hydrochloride from a solvent medium comprising dimethyl sulfoxide and an alcoholic solvent in high purity and in high yield.
The object of the present invention is to provide an improved and commercially viable process for preparation of erlotinib substantially free of N-methoxyethyl impurity, namely N-[(3-ethynylphenyl)-(2-methoxyethyl)]-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine, and its pharmaceutically acceptable acid addition salts thereof in high purity and in high yield.
Another object of the present invention is to provide erlotinib substantially free of N-methoxyethyl impurity, namely N-[(3-ethynylphenyl)-(2-methoxyethyl)]-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, and its pharmaceutically acceptable acid addition salts thereof.